title: α-Galactosylceramide ameliorates autoimmune diabetes in non-obese diabetic mice through a suppressive effect mediated by CD8+ T cells.
abstract: Type 1 diabetes is an autoimmune disorder resulting from lymphocyte-mediated destruction of insulin-producing β cells in pancreas. Natural killer T cells are regulatory immune components controlling autoreactivity and immune homeostasis. Although early studies supported that amelioration of autoimmune diabetes by natural killer T cells was associated with Th1/2 shift, other Th2-independent regulatory mechanisms were also suggested. Since natural killer T cells are critical for the generation of CD8(+) regulatory T cells controlling anterior chamber-associated immune deviation and CD8(+) regulatory T cells also participate in suppression of immune responses like experimental autoimmune encephalomyelitis, we investigate whether the similar suppressive effects are involved in α-galactosylceramide-induced immune tolerance in non-obese diabetic mice. We demonstrate that repeated exposure of α-galactosylceramide reveals a hyporesponsiveness of total or antigen-presenting cells-depleted splenocytes upon anti-CD3/28 antibodies stimulation. The dispensability of dendritic cells in the hyporesponsiveness is consistent with the comparable expression of costimulatory molecules on CD11c(+) subsets between α-galactosylceramide- and vehicle-treated mice. α-Galactosylceramide treatment not only affects the effector T cell subsets and their cytokine production but also increases the secretion of transforming growth factor-β by splenocytes, implying the suppressive regulation. The adoptive transfer experiments demonstrate the suppressive effect of T cells from α-galactosylceramide-treated non-obese diabetic mice when co-transferred with vehicle-treated littermates. Finally, it reveals that CD8(+) subset among antigen-presenting cells-depleted splenocytes tends to confer the suppression since the protective ability vanishes upon withdrawal of CD8(+) subset. These results suggest that repeated exposure of α-galactosylceramide ameliorates autoimmune diabetes in non-obese diabetic mice mediated by CD8(+) T cell-associated suppression.
authors.affiliation: Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Chuang
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D005699:Galactosylceramides; C493154:alpha-galactosylceramide